Study Shows First Genetic Evidence for Schizophrenia
Susceptibility

By Marjorie CentofantiJHMI

A 15-year study in more than 100 families and 1,000 subjects
provides the first reliable evidence of genetic susceptibility to
schizophrenia, within a stretch of DNA on human chromosome 13.
The association of DNA with the susceptibility to the disease,
reported by a Johns Hopkins-led international team, is the first
such linkage to meet stringent statistical standards.

"Finding an actual gene for schizophrenia susceptibility
will be like finding a particular house in a large city," said
genetic epidemiologist Ann Pulver, who led the study. "But we've
found the city. It's a first step, and an exceedingly important
one."

The study, reported in this month's Nature
Genetics, also suggests that different genes may be
responsible for the disease in different families.

Most experts agree schizophrenia is a condition influenced
by both genes and environment. In studies of identical twins, for
example, where only one twin develops schizophrenia, the other
twin has a 46 percent chance of having the disorder. That's
higher than the 1 percent rate for the general population but not
the near 100 percent expected if genes are the only cause. "It's
not the case that if you have the gene, you have the disease,"
Pulver said. "The genetic effect is one of susceptibility to
schizophrenia."

Unlike such inherited disorders as sickle cell anemia, which
stems from mutation in a single gene, susceptibility to
schizophrenia involves more than one gene, Pulver said, as well
as environmental factors.
In the new study, the researchers took and evaluated blood
samples from 54 patients diagnosed with either schizophrenia or
schizoaffective disorder, a type of schizophrenia with elements
of depression, mania or both.
Researchers also took and evaluated samples from patients'
extended families. They extracted blood cell DNA and scanned it
with molecular probes, looking for particular sequences of DNA
that were more likely to appear in those with the mental illness
than those without it. By noting where these markers lay on
chromosomes, the researchers further narrowed the address for the
susceptibility genes. A second study of 51 more families verified
the first results.

The research team also found evidence for susceptibility on
chromosomes 8 and 22, though neither had the statistical strength
of the chromosome 13 area.

Other labs have reported such "linkages" in the past, on
chromosomes 5 and 6. "But there's been a failure to reach high
statistical significance," Pulver said, in part because the
targeted groups of schizophrenic patients were too diverse
genetically. The likelihood of the linkage found on chromosome 13
being due to chance alone, Pulver said, is about two in
100,000.

Many studies show blood relatives of schizophrenia patients
are at risk for several personality disorders as well as for
schizophrenia, Pulver said. A second part of the study suggests
different genes may come into play with different types of the
disorders. Using descriptions of all the family members in the
study, the researchers formed two subgroups: one where at least
one family member had a schizophrenia-like personality disorder
and another where a family member had a mood disorder with
hallucinations and/or delusions.

Then they re-examined the data, focusing on chromosomes 13,
8 and 22. The results showed that families in the study with the
schizophrenic-like personality disorders were more likely to have
genetic ties to chromosomes 8 and 13, whereas those leaning
toward the mood disorder were missing ties to chromosome 8.

"We'd like to see these results repeated," said Pulver,
who's planning new genetic studies on the varied forms of the
disease.